Drug development and CNS 1 Flashcards
What was found wrong with Elixir Sulphanilamide in 1937
Found to be contaminated by diethylene glycol, killing 107 people
What was found wrong with Sulfathiazole in 1941
Cross contamination with phenobarbital causing 300 deaths
What was the thalidomide controvsy in 1960
What was the thalidomide controversy in 1960
Was a sleeping tablet, caused 10,000-20,000 birth defects
What’s the first stage of a clinical trial
Basic research target selection and pre-clinical research
How long does the first stage of a clinical trial take
3- 6 years
What is the second stage of a clinical trial
Clinical research phase 1 (healthy individuals)
Clinical research phase (patients for the first time)
Phase 3
How long does the second stage take
6-7 years
What’s the last stage of a clinical trial and how long does it take
Regulatory review (0.5 - 2 years)
How long and how much money can you spend on a clinical trial
15 years and 1 billion
What are the lead findings in drug trials
Exploring toxicology, safety
How do you create a controlled environment in preclinical development
Providing a safety margin, defining the dose, defining a maximum dose, obtaining regulatory approval of clinical
What does LD50 mean and when was this carried out
Increase the dose until 50% died, in 1920
Now what rule is implemented
3R - reduce, refine, replace
What is the default non rodent
Beagle
What are the three dose groups
Low (no toxicity), intermediate, high
What are the general toxicology’s
Clinical pathology, haematology, kidney and liver function, coagulation
What are the goals for non-clinical safety evaluations
On/ off targets, reversibility, max nontoxic dose and min affective dose, identification of specific monitoring requirements
Examples of withdrawn drugs
Sibutramine (appetite suppressant)
Propoxyphene
Drotecogin
Rimonabant
Hydromorphone
Characteristics of a small molecule drug
Low molecular weight, chemically synthesised, well-defined structure
Characteristics of a biological molecule and monoclonal antibodies
High molecular weight, derived from living organisms, large and complex structure
How much have biologics accounted for in new medicine approvals
one third
Examples of vaccines
HPV, COVID-19
What are RNAi
interfering RNA molecules
What are cell based therapies
Taking a whole cell out of a patient, modify then grow. Then inject back into patient
Example for when cell based therapies are useful
Children with acute lymphoblastic leukemi
Example of when cell based therapies are useful
Children with acute lymphoblastic leukaemia
What is the phase 1 dose
Minimum anticipated biological effect
What is immunotherapy
A form of cancer treatment, uses immune system to attack cancer cells
What do checkpoint inhbitors do
Release natural brake on your immune system so that immune cells called t cells recognise and attack tumors
What do checkpoint inhbitors do
Release natural brake on your immune system so that immune cells called t cells recognise and attack tumours
What is CAR T cell therapy
Scientists engineer a patient’s own immune cells to make a new protein
Who discovered nitrous oxide and when
Horace Wells in the mid 1800s
How are general anaesthetics characterised
By how the chemicals are administered to induce a state of anaesthesia
What are chemical inhalational anaesthetics and example
Nitrous oxide and through the lungs
What are intravenous anaesthetics and example
Administered directly into the circulation system and steroids, barbitruates and halogenated hydrocarbions
Whay are ethers and chloroform not used anymore
They can vapourise at low temperatures and are highly explosive and flammable
What are physical anesthetics
Low pressure (atmospheric) and cold temperatures such as hypothermia
What is the lipid theory of general anaesthetics
The idea that somehow these drugs cause membrane expansion
What is the Meyer- overton rule
The anaesthetic effect was considered proportional to the molar concentratiof the agent in lipid
What are the problems with the lipid theory of general anaesthetics
There’s no temperature effect, no binding sites, no loss of activity with homologoys series of lipophilic compounds and no increase in GABA A
What do low concentrations of volatile gases activate
Two pore domain K channels
What does ketamine and nitrous oxide block
NDMS receptors
What does an increase in inhibitory neurotransmission through GABA A receptors lead to
Inhibition in neural networks
What does an increase in inhibitory neurotranmission of reticular formation lead to
Unconciousness
What does an increase in inhibitory neurotransmission through the hippocampus lead to
Short term memory loss/ amnesia
What happens as the concetration of anesthetics is increased
Inhibition in the CNS, leading to loss of motor control, absejce of artificial respiration leading to death
4 stages of anaesthesia
- Analgesia
- Excitement state
- Surgical aneasthesia
- Medullary paralysis
What are the ideal conditons from anaestheia
Rapid induction and loss of conciousnes, good analgesia, muscle relaxation, rapid recovy
Advantages of intravenous anaesthetics
Easy to administer, rapid induction, short duration of action
Disdvantages of intravenous anaesthetics
Pain at the site of infection, complex pharmacokinetics
Disadvantages of thiopental and what is it an example of
A barbituate intravenous drug. It has a high lipid soluability, low therapeutic index
Side effects of intravenous drugs
Respitary depression, cardiovascular deprssion
What is ketamine
A dissociative anaesthetic
What does ketamine do
Causes sensory loss, powerful analgesic, causes amnesia
What are the side effects of ketamine
Increased CV excitement, involuntary movements, increased intracranial pressure, hallucinations, delirium, irrational behaviour
What is ketamine used for
In pediatrics (with BZD) and vetinary, starting to be used for depression in adults
Examples of inhalational anaesthetics
Isoflurane, desflurane and sevoflurane
Examples of inhalational anaesthetics
Isoflurane, desflurane and sevoflurane
What are anxiolytics
Drugs used to treat anxiety
What are hypnotics
Drugs used to treat sleep disorders
What hormone is secreted when fear response is activated
Cortisol
What is a fear response characterised by
Defensive behaviours, autonomic reflexes, alertness, corticosteroid secretion and negative emotions
Examples of anxiety disorders
Panic disorder, phobias, social anxiety, PTSD, OCD, generalised anxiety
Treatments for anxiety
Benzodiazepines and barbiturates, antidepressants, antiepileptics and antipsychotics
Examples of animal models of anxiety
Elevated cross test, the light/ dark box
What are GABA A receptors targets for
Anxioltyics and hypnotics
What is a GABA A receptor
A lingand gated ion channel
What is a GABA B receptor
A g coupled receptor
What is picrotoxin
A non competitive agonist of the GABA receptor by blocking the pore
What is the second site at the GABA receptor known as
The positive allosteric regulator
What does the allosteric modulator do
Doesn’t activate receptor on its own, it modifies the behaviour of the receptor when agonist is bound to the orthostatic site
What are the physiological effects of the benzodiapene agonists
Sedation, hypnosis, anterograde amnesia, anti- convulsant, reduction of muscle tone
What are the adverse effects of benzodiapene agonists
Decreased tolerance due to increased exposure, misuse, physical dependance,
What is epivario useful for
Post traumatic stress disorder- prevents the consolidation of the memory
